Dimethyltryptamine analogues as nitric oxide delivery drugs

ABSTRACT

Provided herein are compounds of Formula (I), (II), or a pharmaceutically acceptable salt thereof. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), (II), or pharmaceutically acceptable salt thereof, and methods of using a compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of priority to U.S.Provisional Application No. 63/295,199, filed Dec. 30, 2021, thecontents of which are hereby incorporated by reference in its entirety.

BRIEF SUMMARY OF THE INVENTION

In embodiments, the present disclosure provides dimethyltryptaminederivatives that release nitric oxide (NO) in vivo.

In embodiments, the present disclosure provides prodrugs ofdimethyltryptamine and derivatives thereof.

In embodiments, the present disclosure provides compounds of Formula(I), Formula (II), or pharmaceutically acceptable salts thereof.

In embodiments, the present disclosure provides a compound of Formula(I):

or a pharmaceutically acceptable salt thereof; wherein,R₁, R₃, R₄ and R₅ are independently H, halogen, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂;each R₂ is independently C₁-C₆ alkyl;X, Y, and Z are independently absent, H, O, S, NH and —O—(P═O)OHO—;R₇ and R₇′ are independently H, halogen, or C₁-C₆ alkyl;m is 2, 3, or 4;each n is independently 1, 2, 3, 4 or 5; andA⁻ is a pharmaceutically acceptable anion,wherein at least one of R₁, R₃, R₄ and R₅ are —(C═O)(CR₇R₇′)_(n)—ONO₂ or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments, the present disclosure provides a compound of Formula(II):

or a pharmaceutically acceptable salt thereof; wherein,R₃, R₄, and R₅ are independently H, halogen, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂;R₁ and R₆ are independently H, C₁-C₆ alkyl, —(C═O)(CH₂)_(l)—ONO₂;—(C═O)(CH₂)_(m)—CH(NH₂)CH₂ONO₂;R₂ is H or C₁-C₆ alkyl;R₇ and R₇′ are independently H, halogen, or C₁-C₆ alkyl;X, Y, and Z are independently absent, O, S, NH and —O—(P═O)OHO—,m is 2, 3, or 4; andeach n is independently 1, 2, 3, 4 or 5;wherein at least one of R₁, R₃, R₄, R₅ and R₆ is—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments, the present disclosure provides a pharmaceuticalcomposition, comprising a compound of the present disclosure (e.g.,compounds of Formula (I), (II) or Table 1) and a pharmaceuticallyacceptable excipient.

In embodiments, the present disclosure provides methods of using one ormore compounds of the present disclosure (e.g., compounds of Formula(I), (II) or Table 1), e.g., as NO delivery agents.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this disclosure, various patents, patent applications andpublications are referenced. The disclosures of these patents, patentapplications and publications in their entireties are incorporated intothis disclosure by reference for all purposes in order to more fullydescribe the state of the art as known to those skilled therein as ofthe date of this disclosure. This disclosure will govern in the instancethat there is any inconsistency between the patents, patent applicationsand publications cited and this disclosure.

Definitions

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

The terms “administer,” “administering” or “administration” as usedherein refer to administering a compound or pharmaceutically acceptablesalt of the compound or a composition or formulation comprising thecompound or pharmaceutically acceptable salt of the compound to apatient.

The term “treating” as used herein with regard to a patient or subject,refers to improving at least one symptom of the patient's or subject'sdisorder. In some embodiments, treating can be improving, or at leastpartially ameliorating a disorder or one or more symptoms of a disorder.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical formulation that issufficient to result in a desired clinical benefit after administrationto a patient or subject in need thereof.

The term “pharmaceutically acceptable salts” includes both acid and baseaddition salts. Pharmaceutically acceptable salts include those obtainedby reacting the active compound functioning as a base, with an inorganicor organic acid to form a salt, for example, salts of hydrochloric acid,sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonicacid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid,hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylicacid, mandelic acid, carbonic acid, etc. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmaceutically acceptable anions, including but not limitedto malate, oxalate, chloride, bromide, iodide, nitrate, acetate,tartrate, oleate, fumarate, formate, benzoate, glutamate,methanesulfonate, benzenesulfonate, and p-toluenesulfonate salts. Baseaddition salts include but are not limited to, ethylenediamine,N-methyl-glucamine, lysine, arginine, ornithine, choline,N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine, diethylamine, piperazine,tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide,triethylamine, dibenzylamine, ephenamine, dehydroabietylamine,N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, ethylamine, basic aminoacids, e. g., lysine and arginine dicyclohexylamine and the like.Examples of metal salts include lithium, sodium, potassium, magnesium,calcium salts and the like. Examples of ammonium and alkylated ammoniumsalts include ammonium, methylammonium, dimethylammonium,trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium,butylammonium, tetramethylammonium salts and the like. Examples oforganic bases include lysine, arginine, guanidine, diethanolamine,choline and the like. Those skilled in the art will further recognizethat acid addition salts may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example, “C₁-C₆ alkyl” is intendedto encompass C₁, C₂, C₃, C₄, C₅, C₆, C₁-6, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” or “alkyl group” refers to a fully saturated, straight orbranched hydrocarbon chain having from one to twelve carbon atoms, andwhich is attached to the rest of the molecule by a single bond. Alkylscomprising any number of carbon atoms from 1 to 12 are included. Analkyl comprising up to 12 carbon atoms is a C₁-C₁₂ alkyl, an alkylcomprising up to 10 carbon atoms is a C₁-C₁₀ alkyl, an alkyl comprisingup to 6 carbon atoms is a C₁-C₆ alkyl and an alkyl comprising up to 5carbon atoms is a C₁-C₅ alkyl. A C₁-C₅ alkyl includes C₅ alkyls, C₄alkyls, C₃ alkyls, C₂ alkyls and C₁ alkyl (i.e., methyl). A C₁-C₆ alkylincludes all moieties described above for C₁-C₅ alkyls but also includesC₆ alkyls. A C₁-C₁₀ alkyl includes all moieties described above forC₁-C₅ alkyls and C₁-C₆ alkyls, but also includes C₇, C₈, C₉ and C₁₀alkyls. Similarly, a C₁-C₁₂ alkyl includes all the foregoing moieties,but also includes C₁₁ and C₁₂ alkyls. Non-limiting examples of C₁-C₁₂alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless statedotherwise specifically in the specification, an alkyl group can beoptionally substituted.

The term “substituted” used herein means any of the groups describedherein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl,cycloalkenyl, haloalkyl, heterocyclyl, and/or heteroaryl) wherein atleast one hydrogen atom is replaced by a bond to a non-hydrogen atomssuch as, but not limited to: a halogen atom such as F, Cl, Br, and I; anoxygen atom in groups such as hydroxyl groups, alkoxy groups, and estergroups; a sulfur atom in groups such as thiol groups, thioalkyl groups,sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atomin groups such as amines, amides, alkylamines, dialkylamines,arylamines, alkylarylamines, diarylamines, N-oxides, imides, andenamines; a silicon atom in groups such as trialkylsilyl groups,dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilylgroups; and other heteroatoms in various other groups. “Substituted”also means any of the above groups in which one or more hydrogen atomsare replaced by a higher-order bond (e.g., a double- or triple-bond) toa heteroatom such as oxygen in oxo, carbonyl, carboxyl, and estergroups; and nitrogen in groups such as imines, oximes, hydrazones, andnitriles. For example, “substituted” includes any of the above groups inwhich one or more hydrogen atoms are replaced with —NR_(g)R_(h),—NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(O)OR_(h),—NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g),—SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h).“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced with —C(═O)R_(g), —C(═)OR_(g),—C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h). In the foregoing,R_(g) and R_(h) are the same or different and independently hydrogen,alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl,haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,heteroaryl, N-heteroaryl and/or heteroarylalkyl. “Substituted” furthermeans any of the above groups in which one or more hydrogen atoms arereplaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo,thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl,aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl,haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkylgroup. In addition, each of the foregoing substituents can also beoptionally substituted with one or more of the above substituents.

Compounds

In embodiments, the present disclosure provides dimethyltryptaminederivatives that release nitric oxide (NO) in vivo. In embodiments, thepresent disclosure provides prodrugs of dimethyltryptamine andderivatives thereof. In embodiments, the present disclosure providescompound of Formula (I) and (II), or pharmaceutically acceptable saltsthereof.

In embodiments, the present disclosure provides a compound of Formula(I):

or a pharmaceutically acceptable salt thereof; wherein,R₁, R₃, R₄ and R₅ are independently H, halogen, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂;R₂ is independently C₁-C₆ alkyl;X, Y, and Z are independently absent, H, O, S, NH and —O—(P═O)OHO—;m is 2, 3, or 4;each n is independently 1, 2, 3, 4 or 5; andA⁻ is a pharmaceutically acceptable anion,wherein at least one of R₁, R₃, R₄ and R₅ are —(C═O)(CR₇R₇′)_(n)—ONO₂ or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (I), R₁ is C₁-C₆ alkyl. Inembodiments of the compounds of Formula (I), R₁ is methyl, ethyl, orpropyl. In embodiments of the compounds of Formula (I), R₁ is methyl. Inembodiments of the compounds of Formula (I), R₁ is H.

In embodiments of the compounds of Formula (I), R₁ is C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₁ is H,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₁ is H, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (I), R₁ is H, C₁-C₆ alkyl, or —(C═O)(CR₇R₇′)_(n)—ONO₂. Inembodiments of the compounds of Formula (I), R₁ is—(C═O)(CR₇R₇′)_(n)—ONO₂ or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₁ is C₁-C₆ alkyl or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (I), R₁ is halogen, C₁-C₆ alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (I), R₁ is—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula (I),R₁ is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compoundsof Formula (I), R₁ is —(C═O)(CH₂)_(n)—ONO₂. In embodiments of thecompounds of Formula (I), R₁ is —(C═O)(CH₂)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₁ is —(C═O)(CH₂)₃—ONO₂. Inembodiments of the compounds of Formula (I), R₁ is—(C═O)(CH₂)₂—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (I), R₃ is H. In embodimentsof the compounds of Formula (I), R₃ is halogen. In embodiments of thecompounds of Formula (I), R₃ is C₁-C₆ alkyl.

In embodiments of the compounds of Formula (I), R₃ is H, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₃ is H, halogen,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₃ is H, halogen, C₁-C₆alkyl, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of thecompounds of Formula (I), R₃ is H, halogen, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula (I),R₃ is H, halogen, or C₁-C₆ alkyl. In embodiments of the compounds ofFormula (I), R₃ is H or halogen. In embodiments of the compounds ofFormula (I), R₃ is H or C₁-C₆ alkyl. In embodiments of the compounds ofFormula (I), R₃ is halogen or C₁-C₆ alkyl.

In embodiments of the compounds of Formula (I), R₃ is—(C═O)(CR₇R₇′)_(n)—ONO₂ or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₃ is—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula (I),R₃ is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (I), R₄ is H, halogen, orC₁-C₆ alkyl. In embodiments of the compounds of Formula (I), R₄ is H orhalogen. In embodiments of the compounds of Formula (I), R₄ is H orC₁-C₆ alkyl. In embodiments of the compounds of Formula (I), R₄ ishalogen or C₁-C₆ alkyl.

In embodiments of the compounds of Formula (I), R₄ is halogen, C₁-C₆alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₄ is H, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₄ is H, halogen,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₄ is H, halogen, C₁-C₆alkyl, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of thecompounds of Formula (I), R₄ is H, halogen, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(n)—ONO₂.

In embodiments of the compounds of Formula (I), R₄ is—(C═O)(CR₇R₇′)_(n)—ONO₂ or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₄ is—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula (I),R₄ is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (I), R₅ is H. In embodimentsof the compounds of Formula (I), R₅ is halogen. In embodiments of thecompounds of Formula (I), R₅ is C₁-C₆ alkyl. In embodiments of thecompounds of Formula (I), R₅ is H, halogen, or C₁-C₆ alkyl.

In embodiments of the compounds of Formula (I), R₅ is H or halogen. Inembodiments of the compounds of Formula (I), R₅ is H or C₁-C₆ alkyl. Inembodiments of the compounds of Formula (I), R₅ is halogen or C₁-C₆alkyl.

In embodiments of the compounds of Formula (I), R₅ is halogen, C₁-C₆alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₅ is H, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₅ is H, halogen,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₅ is H, halogen, C₁-C₆alkyl, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of thecompounds of Formula (I), R₅ is H, halogen, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(n)—ONO₂.

In embodiments of the compounds of Formula (I), R₅ is—(C═O)(CR₇R₇′)_(n)—ONO₂ or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (I), R₅ is—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula (I),R₅ is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (I), R₇ and R₇′ independentlyH or C₁-C₆ alkyl. In embodiments of the compounds of Formula (I), R₇ andR₇′ independently H or C₁-C₃ alkyl. In embodiments of the compounds ofFormula (I), R₇ and R₇′ independently H or halogen alkyl. In embodimentsof the compounds of Formula (I), R₇ and R₇′ independently halogen orC₁-C₆ alkyl. In embodiments of the compounds of Formula (I), R₇ and R₇′independently halogen or C₁-C₃ alkyl.

In embodiments of the compounds of Formula (I), X is O, S, NH and—O—(P═O)OHO—. In embodiments of the compounds of Formula (I), X isabsent, S, NH and —O—(P═O)OHO—. In embodiments of the compounds ofFormula (I), X is absent, O, S or —O—(P═O)OHO—. In embodiments of thecompounds of Formula (I), X is absent, O, S, or NH. In embodiments ofthe compounds of Formula (I), X is O or —O—(P═O)OHO—.

In embodiments of the compounds of Formula (I), X is absent. Inembodiments of the compounds of Formula (I), X is O. In embodiments ofthe compounds of Formula (I), X is S. In embodiments of the compounds ofFormula (I), X is NH. In embodiments of the compounds of Formula (I), Xis —O—(P═O)OHO—.

In embodiments of the compounds of Formula (I), Y is O, S, NH and—O—(P═O)OHO—. In embodiments of the compounds of Formula (I), Y isabsent, S, NH and —O—(P═O)OHO—. In embodiments of the compounds ofFormula (I), Y is absent, O, S or —O—(P═O)OHO—. In embodiments of thecompounds of Formula (I), Y is absent, O, S, or NH. In embodiments ofthe compounds of Formula (I), Y is O or —O—(P═O)OHO—.

In embodiments of the compounds of Formula (I), Y is absent. Inembodiments of the compounds of Formula (I), Y is O. In embodiments ofthe compounds of Formula (I), Y is S. In embodiments of the compounds ofFormula (I), Y is NH. In embodiments of the compounds of Formula (I), Yis —O—(P═O)OHO—.

In embodiments of the compounds of Formula (I), Z is O, S, NH and—O—(P═O)OHO—. In embodiments of the compounds of Formula (I), Z isabsent, S, NH and —O—(P═O)OHO—. In embodiments of the compounds ofFormula (I), Z is absent, O, S or —O—(P═O)OHO—. In embodiments of thecompounds of Formula (I), Z is absent, O, S, or NH. In embodiments ofthe compounds of Formula (I), Z is O or —O—(P═O)OHO—.

In embodiments of the compounds of Formula (I), Z is absent. Inembodiments of the compounds of Formula (I), Z is O. In embodiments ofthe compounds of Formula (I), Z is S. In embodiments of the compounds ofFormula (I), Z is NH. In embodiments of the compounds of Formula (I), Zis —O—(P═O)OHO—.

In embodiments of the compounds of Formula (I), n is 1. In embodimentsof the compounds of Formula (I), n is 2. In embodiments of the compoundsof Formula (I), n is 3. In embodiments of the compounds of Formula (I),n is 4. In embodiments of the compounds of Formula (I), n is 5.

In embodiments of the compounds of Formula (I), m is 2. In embodimentsof the compounds of Formula (I), m is 3. In embodiments of the compoundsof Formula (I), m is 4. In embodiments of the compounds of Formula (I),m is 5.

In embodiments of the compounds of Formula (I), R₃ is H and X is absent.In embodiments of compounds of Formula (I), R₃ is halogen and X isabsent. In embodiments of compounds of Formula (I), R₃ is H and X is O.In embodiments of compounds of Formula (I), R₃ is C₁-C₆ alkyl and X isO. In embodiments of compounds of Formula (I), R₃ is C₁, F, Br, or I andX is absent. In embodiments of compounds of Formula (I), R₃ is F and Xis absent.

In embodiments of the compounds of Formula (I), R₄ is H and Y is absent.In embodiments of compounds of Formula (I), R₄ is halogen and Y isabsent. In embodiments of compounds of Formula (I), R₄ is H and Y is O.In embodiments of compounds of Formula (II), R₄ is C₁-C₆ alkyl and Y isO. In embodiments of compounds of Formula (I), R₄ is C₁, F, Br, or I andY is absent. In embodiments of compounds of Formula (I), R₄ is F and Yis absent

In embodiments of the compounds of Formula (I), R₅ is H and Z is absent.In embodiments of compounds of Formula (I), R₅ is halogen and Z isabsent. In embodiments of compounds of Formula (I), R₅ is H and Z is O.In embodiments of compounds of Formula (I), R₅ is C₁-C₆ alkyl and Z isO. In embodiments of compounds of Formula (I), R₅ is C₁, F, Br, or I andZ is absent. In embodiments of compounds of Formula (II), R₅ is F and Zis absent.

Formula (II):

In embodiments, provided herein is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein,R₃, R₄, and R₅ are independently H, halogen, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂;R₁ and R₆ are independently H, C₁-C₆ alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂;R₂ is H or C₁-C₆ alkyl; andR₇ and R₇′ are independently H, halogen, or C₁-C₆ alkyl;X, Y, and Z are independently absent, O, S, NH and —O—(P═O)OHO—,m is 2, 3, or 4; andeach n is independently 1, 2, 3, 4 or 5;wherein at least one of R₁, R₃, R₄, R₅ and R₆ is—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₁ is C₁-C₆ alkyl. Inembodiments of the compounds of Formula (II), R₁ is methyl, ethyl, orpropyl. In embodiments of the compounds of Formula (II), R₁ is methyl.In embodiments of the compounds of Formula (II), R₁ is H.

In embodiments of the compounds of Formula (II), R₁ is—(C═O)(CR₇R₇′)_(n)—ONO₂.

In embodiments of the compounds of Formula (II), R₁ is—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₁ is —(C═O)(CH₂)_(n)—ONO₂. In embodiments of thecompounds of Formula (II), R₁ is —(C═O)(CH₂)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₁ is —(C═O)(CH₂)₃—ONO₂.In embodiments of the compounds of Formula (II), R₁ is—(C═O)(CH₂)₂—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₁ is C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₁ is H,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₁ is H, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₁ is H, C₁-C₆ alkyl, or —(C═O)(CR₇R₇′)_(n)—ONO₂. Inembodiments of the compounds of Formula (II), R₁ is—(C═O)(CR₇R₇′)_(n)—ONO₂ or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₁ is C₁-C₆ alkyl or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₁ is C₁-C₆ alkyl, or —(C═O)(is halogen, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₃ is H, halogen, orC₁-C₆ alkyl. In embodiments of the compounds of Formula (II), R₃ is H orhalogen. In embodiments of the compounds of Formula (II), R₃ is H orC₁-C₆ alkyl. In embodiments of the compounds of Formula (II), R₃ ishalogen or C₁-C₆ alkyl. In embodiments of the compounds of Formula (II),R₃ is H. In embodiments of the compounds of Formula (II), R₃ is halogen.In embodiments of the compounds of Formula (II), R₃ is C₁-C₆ alkyl.

In embodiments of the compounds of Formula (II), R₃ is H, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₃ is H, halogen,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₃ is H, halogen, C₁-C₆alkyl, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of thecompounds of Formula (II), R₃ is H, halogen, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula(II), R₃ is —(C═O)(CR₇R₇′)_(n)—ONO₂ or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₃ is —(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of thecompounds of Formula (II), R₃ is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₄ is H, halogen, orC₁-C₆ alkyl. In embodiments of the compounds of Formula (II), R₄ is H orhalogen. In embodiments of the compounds of Formula (II), R₄ is H orC₁-C₆ alkyl. In embodiments of the compounds of Formula (II), R₄ ishalogen or C₁-C₆ alkyl.

In embodiments of the compounds of Formula (II), R₄ is halogen, C₁-C₆alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₄ is H, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₄ is H, halogen,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₄ is H, halogen, C₁-C₆alkyl, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of thecompounds of Formula (II), R₄ is H, halogen, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula(II), R₄ is —(C═O)(CR₇R₇′)_(n)—ONO₂ or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₄ is —(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of thecompounds of Formula (II), R₄ is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₅ is H, halogen, orC₁-C₆ alkyl. In embodiments of the compounds of Formula (II), R₅ is H orhalogen. In embodiments of the compounds of Formula (II), R₅ is H orC₁-C₆ alkyl. In embodiments of the compounds of Formula (II), R₅ ishalogen or C₁-C₆ alkyl. In embodiments of the compounds of Formula (II),R₅ is H. In embodiments of the compounds of Formula (II), R₅ is halogen.In embodiments of the compounds of Formula (II), R₅ is C₁-C₆ alkyl.

In embodiments of the compounds of Formula (II), R₅ is halogen, C₁-C₆alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₅ is H, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₅ is H, halogen,—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₅ is H, halogen, C₁-C₆alkyl, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of thecompounds of Formula (II), R₅ is H, halogen, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula(II), R₅ is —(C═O)(CR₇R₇′)_(n)—ONO₂ or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₅ is —(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of thecompounds of Formula (II), R₅ is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₆ is H or C₁-C₆ alkyl.In embodiments of the compounds of Formula (II), R₆ is C₁-C₆ alkyl. Inembodiments of the compounds of Formula (II), R₆ is methyl, ethyl, orpropyl. In embodiments of the compounds of Formula (II), R₆ is methyl.

In embodiments of the compounds of Formula (II), R₆ is H.In embodiments of the compounds of Formula (II), R₆ is—(C═O)(CR₇R₇′)_(n)—ONO₂.

In embodiments of the compounds of Formula (II), R₆ is—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₆ is —(C═O)(CH₂)_(n)—ONO₂. In embodiments of thecompounds of Formula (II), R₆ is —(C═O)(CH₂)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₆ is —(C═O)(CH₂)₃—ONO₂.In embodiments of the compounds of Formula (II), R₆ is—(C═O)(CH₂)₂—CH(NH₂)CH₂ONO₂. In embodiments of the compounds of Formula(II), R₆ is C₁-C₆ alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₆ is H, —(C═O)(CR₇R₇′)_(n)—ONO₂, or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₆ is H, C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. In embodiments of the compounds ofFormula (II), R₆ is H, C₁-C₆ alkyl, or —(C═O)(CR₇R₇′)_(n)—ONO₂. Inembodiments of the compounds of Formula (II), R₆ is—(C═O)(CR₇R₇′)_(n)—ONO₂ or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂. Inembodiments of the compounds of Formula (II), R₆ is C₁-C₆ alkyl or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₆ is C₁-C₆ alkyl, or—(C═O)(CR₇R₇′)_(n)—ONO₂. In embodiments of the compounds of Formula(II), R₆ is H or —(C═O)(CR₇R₇′)_(n)—ONO₂.

In embodiments of the compounds of Formula (II), R₆ is H or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.

In embodiments of the compounds of Formula (II), R₇ and R₇′independently H or C₁-C₆ alkyl. In embodiments of the compounds ofFormula (II), R₇ and R₇′ independently H or C₁-C₃ alkyl. In embodimentsof the compounds of Formula (II), R₇ and R₇′ independently H or halogenalkyl. In embodiments of the compounds of Formula (II), R₇ and R₇′independently halogen or C₁-C₆ alkyl. In embodiments of the compounds ofFormula (II), R₇ and R₇′ independently halogen or C₁-C₃ alkyl.

In embodiments of the compounds of Formula (II), X is O, S, NH and—O—(P═O)OHO—. In embodiments of the compounds of Formula (II), X isabsent, S, NH and —O—(P═O)OHO—. In embodiments of the compounds ofFormula (II), X is absent, O, S or —O—(P═O)OHO—. In embodiments of thecompounds of Formula (II), X is absent, O, S, or NH. In embodiments ofthe compounds of Formula (II), X is absent. In embodiments of thecompounds of Formula (II), X is O. In embodiments of the compounds ofFormula (II), X is S. In embodiments of the compounds of Formula (II), Xis NH. In embodiments of the compounds of Formula (II), X is—O—(P═O)OHO—. In embodiments of the compounds of Formula (II), X is O or—O—(P═O)OHO—.

In embodiments of the compounds of Formula (II), Y is O, S, NH and—O—(P═O)OHO—. In embodiments of the compounds of Formula (II), Y isabsent, S, NH and —O—(P═O)OHO—. In embodiments of the compounds ofFormula (II), Y is absent, O, S or —O—(P═O)OHO—. In embodiments of thecompounds of Formula (II), Y is absent, O, S, or NH. In embodiments ofthe compounds of Formula (II), Y is absent. In embodiments of thecompounds of Formula (II), Y is O. In embodiments of the compounds ofFormula (II), Y is S. In embodiments of the compounds of Formula (II), Yis NH. In embodiments of the compounds of Formula (II), Y is—O—(P═O)OHO—. In embodiments of the compounds of Formula (II), Y is O or—O—(P═O)OHO—.

In embodiments of the compounds of Formula (II), Z is O, S, NH and—O—(P═O)OHO—. In embodiments of the compounds of Formula (II), Z isabsent, S, NH and —O—(P═O)OHO—. In embodiments of the compounds ofFormula (II), Z is absent, O, S or —O—(P═O)OHO—. In embodiments of thecompounds of Formula (II), Z is absent, O, S, or NH. In embodiments ofthe compounds of Formula (II), Z is absent. In embodiments of thecompounds of Formula (II), Z is O. In embodiments of the compounds ofFormula (II), Z is S. In embodiments of the compounds of Formula (II), Zis NH. In embodiments of the compounds of Formula (II), Z is—O—(P═O)OHO—. In embodiments of the compounds of Formula (II), Z is O or—O—(P═O)OHO—.

In embodiments of the compounds of Formula (II), n is 1. In embodimentsof the compounds of Formula (II), n is 2. In embodiments of thecompounds of Formula (II), n is 3. In embodiments of the compounds ofFormula (II), n is 4. In embodiments of the compounds of Formula (II), nis 5.

In embodiments of the compounds of Formula (II), m is 2. In embodimentsof the compounds of Formula (II), m is 3. In embodiments of thecompounds of Formula (II), m is 4. In embodiments of the compounds ofFormula (II), m is 5.

In embodiments of the compounds of Formula (II), R₃ is H and X isabsent. In embodiments of compounds of Formula (II), R₃ is halogen and Xis absent. In embodiments of compounds of Formula (II), R₃ is H and X isO. In embodiments of compounds of Formula (II), R₃ is C₁-C₆ alkyl and Xis O. In embodiments of compounds of Formula (II), R₃ is C₁, F, Br, or Iand X is absent. In embodiments of compounds of Formula (II), R₃ is Fand X is absent.

In embodiments of the compounds of Formula (II), R₄ is Hand Y is absent.In embodiments of compounds of Formula (II), R₄ is halogen and Y isabsent. In embodiments of compounds of Formula (II), R₄ is H and Y is O.In embodiments of compounds of Formula (II), R₄ is C₁-C₆ alkyl and Y isO. In embodiments of compounds of Formula (II), R₄ is C₁, F, Br, or Iand Y is absent. In embodiments of (compounds of Formula (II), R₄ is Fand Y is absent.

In embodiments of the compounds of Formula (II), R₅ is H and Z isabsent. In embodiments of compounds of Formula (II), R₅ is halogen and Zis absent. In embodiments of compounds of Formula (II), R₅ is H and Z isO. In embodiments of compounds of Formula (II), R₅ is C₁-C₆ alkyl and Zis O. In embodiments of compounds of Formula (II), R₅ is C₁, F, Br, or Iand Z is absent.

In embodiments of compounds of Formula (II), R₅ is F and Z is absent.

TABLE 1 Compounds of Formula (II) No. Structure  2-1

4-(3-(2- (dimethylamino)ethyl)-1H- indol-1-yl)-4-oxobutyl nitrate  2-2

5-(3-(2- (dimethylamino)ethyl)-1H- indol-1-yl)-5-oxopentyl nitrate  2-3

2-(chloro-λ⁵-azaneyl)-5-(3- (2-(dimethylamino)ethyl)-1H-indol-1-yl)-5-oxopentyl nitrate  2-4

2-amino-5-(3-(2- (dimethylamino)ethyl)-1H- indol-1-yl)-5-oxopentylnitrate  2-5

4-(3-(2- (dimethylamino)ethyl)-5- methoxy-1H-indol-1-yl)-4- oxobutylnitrate 2-6

4-(3-(2- (dimethylamino)ethyl)-5- fluoro-1H-indol-1-yl)-4- oxobutylnitrate 2-7

4-(3-(2- (dimethylamino)ethyl)-4- hydroxy-1H-indol-1-yl)-4- oxobutylnitrate 2-8

4-(3-(2- (ethyl(methyl)amino)ethyl)-5- fluoro-1H-indol-1-yl)-4- oxobutylnitrate  2-9

4-(3-(2-(diethylamino)ethyl)- 5-fluoro-1H-indol-1-yl)-4- oxobutylnitrate 2-10

4-(3-(2- (dimethylamino)ethyl)-1H- indol-l-yl)-3-methyl-4- oxobutylnitrate 2-11

3-amino-4-(3-(2- (dimethylamino)ethyl)-1H- indol-1-yl)-4-oxobutylnitrate 2-12

4-(3-(2- (dimethylamino)ethyl)-5- (methoxy-d₃)-H-indol-1-yl)- 4-oxobutylnitrate 2-13

4-(3-(2- (diisopropylamino)ethyl)-1H- indol-l-yl)-4-oxobutyl nitrate2-14

4-(3-(2-(bis(methyl- d3)amino)ethyl)-1H-indol-1- yl)-4-oxobutyl nitrate

Compositions

In embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a therapeutically effective amount of one or morecompounds of the present disclosure (e.g., a compound of Formula (I),(II), or Table 1) or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.

The pharmaceutically acceptable excipients and adjuvants are added tothe composition or formulation for a variety of purposes. In someembodiments, a pharmaceutical composition comprising one or morecompounds disclosed herein, or a pharmaceutically acceptable saltthereof, further comprise a pharmaceutically acceptable carrier. In someembodiments, a pharmaceutically acceptable carrier includes apharmaceutically acceptable excipient, binder, and/or diluent. In someembodiments, suitable pharmaceutically acceptable carriers include, butare not limited to, inert solid fillers or diluents and sterile aqueousor organic solutions. In some embodiments, suitable pharmaceuticallyacceptable excipients include, but are not limited to, water, saltsolutions, alcohol, polyethylene glycols, gelatin, lactose, amylase,magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

For the purposes of this disclosure, the compounds of the presentdisclosure can be formulated for administration by a variety of meansincluding orally, parenterally, by inhalation spray, topically, orrectally in formulations containing pharmaceutically acceptablecarriers, adjuvants and vehicles. The term parenteral as used hereincludes subcutaneous, intravenous, intramuscular, and intraarterialinjections with a variety of infusion techniques. Intraarterial andintravenous injection as used herein includes administration throughcatheters.

Methods of Treatment

In one aspect, the present disclosure provides methods of treating adisease or disorder in a subject in need thereof, the methods comprisingadministering a therapeutically effective amount of a compound describedherein (e.g., a compound of Formula (I), (II), or Table 1) orpharmaceutically acceptable salt thereof to the subject.

In embodiments, the disease or disorder is a mental health disease ordisorder. In embodiments, the mental health disease or disorder isselected from the group consisting of major depressive disorder,treatment resistant depression, substance use disorders and eatingdisorders.

In embodiments, eating disorders include illnesses such as anorexianervosa, bulimia nervosa, and other disorders related to eating (e.g.,binge eating).

In embodiments, the mental health disease or disorder is an eatingdisorder.

In embodiments, the mental health disease or disorder is selected fromthe group consisting of compulsive disorders, anxiety disorders, stressdisorders, and rumination.

In embodiments, the mental health disease or disorder is a mooddisorder. In embodiments, mood disorders include e.g., depressivedisorders, such as major depressive disorder or treatment resistantdepression.

In embodiments, the mental health disorder is a substance abusedisorder. In embodiments, substance use related disorders are disordersof maladaptive patterns of substance use, and include criteria, such asrecurrent substance use related problems, tolerance to a substance,withdrawal upon discontinuing use, an inability to cut down or controluse of the substance, and giving up important social, occupational, orrecreational activities because of using the substance. See e.g., theDiagnostic and Statistical Manual of Mental Disorders (DSM-5). Inembodiments, the substance use related disorder is a disorder resultingfrom the use of: alcohol; caffeine; cannabis; hallucinogens (such asphencyclidine or similarly acting arylcyclohexylamines, and otherhallucinogens, such as LSD); inhalants; opioids; sedatives, hypnotics,or anxiolytics; stimulants (including amphetamine-type substances,cocaine, and other stimulants); tobacco; and other substances.

In embodiments, administering compounds of the present disclosure (e.g.,a compound of Formula (I), (II), or Table 1) or a pharmaceuticallyacceptable salt thereof releases nitric oxide (NO) (e.g., the compoundsof the present disclosure are NO delivery drugs). In embodiments thecompounds of the present disclosure are useful for releasing NO in vivo.

Numbered Embodiments

In addition to the disclosure above, the Examples below, and theappended claims, the disclosure sets for the following numberedembodiments.

1. A Compound of Formula (II).

or a pharmaceutically acceptable salt thereof; wherein,R₃, R₄, and R₅ are independently H, halogen, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂;R₁ and R₆ are independently H, C₁-C₆ alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂,—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂;R₂ is H or C₁-C₆ alkyl; andR₇ and R₇′ are independently H, halogen, or C₁-C₆ alkyl;X, Y, and Z are independently absent, O, S, NH, or —O—(P═O)OHO—,m is 2, 3, or 4; andeach n is independently 1, 2, 3, 4 or 5;wherein at least one of R₁, R₃, R₄, R₅ and R₆ is—(C═O)(CR₇R₇′)_(n)—ONO₂, —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.2. The compound of embodiment 1, wherein R₁ is C₁-C₆ alkyl.3. The compound of embodiment 1, wherein R₁ is methyl.4. The compound of embodiment 1, wherein R₁ is H.5. The compound of any one of embodiments 1-4, wherein R₂ is C₁-C₆alkyl.6. The compound of any one of embodiments 1-4 wherein R₂ is methyl.7. The compound of any one of embodiments 1-4, wherein R₂ is H.8. The compound of any one of embodiments 1-7, wherein R₃ is H and X isabsent.9. The compound of any one of embodiments 1-7, wherein R₃ is halogen andX is absent.10. The compound of any one of embodiments 1-7, wherein R₃ is H and X isO.11. The compound of any one of embodiments 1-7, wherein R₃ is C₁-C₆alkyl and X is O.12. The compound of any one of embodiments 1-11, wherein R₄ is H and Yis absent.13. The compound of any one of embodiments 1-11, wherein R₄ is H and Yis O.14. The compound of any one of embodiments 1-11, wherein R₄ is halogenand Y is absent.15. The compound of any one of embodiments 1-11, wherein R₄ is C₁-C₆alkyl and Y is O.16. The compound of any one of embodiments 1-15, wherein R₅ is H and Zis absent.17. The compound of any one of embodiments 1-15, wherein R₅ is H and Zis O.18. The compound of any one of embodiments 1-15, wherein R₅ is halogenand Z is absent.19. The compound of any one of embodiments 1-15, wherein R₅ is C₁-C₆alkyl and Z is absent.20. The compound of any one of embodiments 1-15, wherein R₅ is C₁-C₆alkyl and Z is O.21. The compound of any one of embodiments 1-20, wherein R₆ is—(C═O)(CR₇R₇′)_(n)—ONO₂.22. The compound of any one of embodiments 1-20, wherein R₆ is—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.23. The compound of any one of embodiments 1-20, wherein R₆ is—(C═O)(CH₂)_(n)—ONO₂.24. The compound of any one of embodiments 1-20, wherein R₆ is—(C═O)(CH₂)_(m)—CH(NH₂)CH₂ONO₂.25. The compound of any one of embodiments 1-20, wherein R₆ is—(C═O)(CH₂)₃—ONO₂.26. The compound of any one of embodiments 1-25, having the followingchemical formula:

27. The compound of embodiment 26, having the following chemicalformula:

28. The compound of embodiment 26, having the following chemicalformula:

29. A pharmaceutical composition, comprising a compound of any one ofembodiments 1-28 and a pharmaceutically acceptable excipient.30. A method of treating a mental health disease or disorder, the methodcomprising administering a therapeutically effective amount of acompound of any one of embodiments 1-28 or pharmaceutical composition ofembodiment 29.31. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein,R₁, R₃, R₄ and R₅ are independently H, halogen, C₁-C₆ alkyl,—(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂;R₂ is C₁-C₆ alkyl;X, Y, and Z are independently absent, H, O, S, NH and —O—(P═O)OHO—;m is 2, 3, or 4;each n is independently 1, 2, 3, 4 or 5; andA⁻ is a pharmaceutically acceptable anion,wherein at least one of R₁, R₃, R₄ and R₅ are —(C═O)(CR₇R₇′)_(n)—ONO₂ or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.32. The compound of embodiment 31, wherein R₁ is—(C═O)(CR₇R₇′)_(n)—ONO₂.33. The compound of embodiment 31, wherein R₁ is—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.34. The compound of embodiment 31, wherein R₁ is —(C═O)(CH₂)_(n)—ONO₂.35. The compound of embodiment 31, wherein R₁ is—(C═O)(CH₂)_(m)—CH(NH₂)CH₂ONO₂.36. The compound of embodiment 31, wherein R₁ is —(C═O)(CH₂)₃—ONO₂.37. The compound of embodiment 31, wherein R₁ is—(C═O)(CH₂)₂—CH(NH₂)CH₂ONO₂.38. The compound of any one of embodiments 31-37, wherein R₂ is a C₁-C₃alkyl.39. The compound of any one of embodiments 31-38, wherein R₃ is H and Xis absent.40. The compound of any one of embodiments 31-38, wherein R₃ is halogenand X is absent.41. The compound of any one of embodiments 31-38, wherein R₃ is H and Xis O.42. The compound of any one of embodiments 31-38, wherein R₃ is C₁-C₆alkyl and X is O.43. The compound of any one of embodiments 31-42, wherein R₄ is H and Yis absent.44. The compound of any one of embodiments 31-42, wherein R₄ is H and Yis O.45. The compound of any one of embodiments 31-42, wherein R₄ is halogenand Y is absent.46. The compound of any one of embodiments 31-42, wherein R₄ is C₁-C₆alkyl and Y is O.47. The compound of any one of embodiments 31-46, wherein R₅ is H and Zis absent.48. The compound of any one of embodiments 31-46, wherein R₅ is H and Zis O.49. The compound of any one of embodiments 31-46, wherein R₅ is halogenand Z is absent.50. The compound of any one of embodiments 31-46, wherein R₅ is C₁-C₆alkyl and Z is O.51. A pharmaceutical composition, comprising a compound of any one ofembodiments 31-50 and a pharmaceutically acceptable excipient.52. A method of treating a mental health disease or disorder, the methodcomprising administering a therapeutically effective amount of acompound of any one of embodiments 31-50 or pharmaceutical compositionof embodiment 51.

Examples Example 1: Methods of Preparing the Compounds of the PresentDisclosure Synthesis of Compound 2-1

Prodrug 2-1 was synthesized from commercially available intermediate2-1-1 and 2-1-3 in three steps and described in the Scheme 1.

Synthesis of Intermediate 2-1-1

To a stirred solution of methyl 4-bromobutanoate, 2-1-1 (3 g, 16.5 mmol,1.0 equiv) in acetonitrile was added AgNO₃ (7.0 g, 41.4 mmol, 2.5 equiv)in portions at room temperature under argon atmosphere. The resultingmixture was stirred for overnight at 80° C. under argon atmosphere. Newpot could be detected by TLC. The resulting mixture was filtered, thefilter cake was washed with acetonitrile (3×50 mL). The filtrate wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate (500 mL). The resulting mixture was washed with 2×500 mL ofwater. and then the resulting mixture was washed with 3×300 mL of brine.The combined organic layers dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure toafford methyl 4-(nitrooxy)butanoate, 2-1-2 (2.3 g, 85.08%) as a yellowoil. This crude product was used directly for the next step withoutfurther purification.

Synthesis of Intermediate 2-1-4 and final Product1-(3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-4-(nitrooxy)butanoate (2-1)

To a stirred solution of tryptamine (200 mg, 1.2 mmol, 1.0 equiv) andNaBH₃CN (235.3 mg, 3.7 mmol, 3.0 equiv), AcOH (0.2 mL) in MeOH was addedformaldehyde solution (187.4 mg, 6.24 mmol, 5.0 equiv) dropwise at 0° C.under argon atmosphere. The resulting mixture was stirred for overnightat room temperature under argon atmosphere. Desired product could bedetected by LCMS. The resulting mixture was filtered, the filter cakewas washed with MeOH (3×10 mL). The filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EA (1:1) to afford intermediate as ayellow solid. To a stirred solution of intermediate and methyl4-(nitrooxy)butanoate (610.8 mg, 3.7 mmol, 3.0 equiv) in THE was addedLiHMDS (313.3 mg, 1.8 mmol, 1.5 equiv) in THE dropwise at 0° C. underargon atmosphere. The resulting mixture was stirred for 1 h at 0° C.under argon atmosphere. Desired product could be detected by LCMS. Thereaction was quenched with MeOH at 0° C. The resulting mixture wasconcentrated under vacuum. The residue was purified by reversed-phaseflash chromatography with the following conditions: column, C₁₈ silicagel; mobile phase, MeCN in Water (0.1% FA), 5% to 80% gradient in 40min; detector, UV 254 nm. to afford 25 mg of1-(3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-4-(nitrooxy)butanoate (2-1)as a white solid. LCMS of 2-1: [M+H]⁺ 320.10

HNMR-2-1: (400 MHz, DMSO-d6) δ 8.07 (d, J=8.2 Hz, 1H), 7.62 (d, J=7.7Hz, 1H), 7.52 (s, 1H), 7.36-7.25 (m, 2H), 4.79 (t, J=6.7 Hz, 2H), 4.47(t, J=6.0 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.57-2.40 (m, 4H), 2.22 (s,6H).

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein, R₃, R₄, and R₅are independently H, halogen, C₁-C₆ alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂; R₁ and R₆ are independently H, C₁-C₆alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂, or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂; R₂is H or C₁-C₆ alkyl; R₇ and R₇′ are independently H, halogen, or C₁-C₆alkyl; X, Y, and Z are independently absent, O, S, NH, or —O—(P═O)OHO—;each m is 2, 3, or 4; and each n is independently 1, 2, 3, 4 or 5;wherein at least one of R₁, R₃, R₄, R₅, and R₆ is—(C═O)(CR₇R₇′)_(n)—ONO₂ or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.
 2. Thecompound of claim 1, wherein R₁ is C₁-C₆ alkyl.
 3. The compound of claim1, wherein R₁ is methyl.
 4. The compound of claim 1, wherein R₁ is H. 5.The compound of claim 1, wherein R₂ is C₁-C₆ alkyl.
 6. The compound ofclaim 1, wherein R₂ is methyl.
 7. The compound of claim 1, wherein R₂ isH.
 8. The compound of claim 1, wherein R₃ is H and X is absent.
 9. Thecompound of claim 1, wherein R₃ is halogen and X is absent.
 10. Thecompound of claim 1, wherein R₃ is H and X is O.
 11. The compound ofclaim 1, wherein R₃ is C₁-C₆ alkyl and X is O.
 12. The compound of claim1, wherein R₄ is H and Y is absent.
 13. The compound of claim 1, whereinR₄ is H and Y is O.
 14. The compound of claim 1, wherein R₄ is halogenand Y is absent.
 15. The compound of claim 1, wherein R₄ is C₁-C₆ alkyland Y is O.
 16. The compound of claim 1, wherein R₅ is H and Z isabsent.
 17. The compound of claim 1, wherein R₅ is H and Z is O.
 18. Thecompound of claim 1, wherein R₅ is halogen and Z is absent.
 19. Thecompound of claim 1, wherein R₅ is C₁-C₆ alkyl and Z is absent.
 20. Thecompound of claim 1, wherein R₅ is C₁-C₆ alkyl and Z is O.
 21. Thecompound of claim 1, wherein R₆ is —(C═O)(CR₇R₇′)_(n)—ONO₂.
 22. Thecompound of claim 1, wherein R₆ is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.23. The compound of claim 1, wherein R₆ is —(C═O)(CH₂)_(n)—ONO₂.
 24. Thecompound of claim 1, wherein R₆ is —(C═O)(CH₂)_(m)—CH(NH₂)CH₂ONO₂. 25.The compound of claim 1, wherein R₆ is —(C═O)(CH₂)₃—ONO₂.
 26. Thecompound of claim 1, having the following chemical formula:


27. The compound of claim 26, having the following chemical formula:


28. The compound of claim 26, having the following chemical formula:


29. A pharmaceutical composition, comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 30. A method of treating a mentalhealth disease or disorder, the method comprising administering atherapeutically effective amount of a compound of claim 1 to a patientin need thereof.
 31. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein, R₁, R₃, R₄, andR₅ are independently H, halogen, C₁-C₆ alkyl, —(C═O)(CR₇R₇′)_(n)—ONO₂,or —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂; each R₂ is independently C₁-C₆alkyl; X, Y, and Z are independently absent, H, O, S, NH, or—O—(P═O)OHO—; each m is 2, 3, or 4; each n is independently 1, 2, 3, 4,or 5; and A⁻ is a pharmaceutically acceptable anion, wherein at leastone of R₁, R₃, R₄, and R₅ is —(C═O)(CR₇R₇′)_(n)—ONO₂ or—(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.
 32. The compound of claim 31, whereinR₁ is —(C═O)(CR₇R₇′)_(n)—ONO₂.
 33. The compound of claim 31, wherein R₁is —(C═O)(CR₇R₇′)_(m)—CH(NH₂)CH₂ONO₂.
 34. The compound of claim 31,wherein R₁ is —(C═O)(CH₂)_(n)—ONO₂.
 35. The compound of claim 31,wherein R₁ is —(C═O)(CH₂)_(m)—CH(NH₂)CH₂ONO₂.
 36. The compound of claim31, wherein R₁ is —(C═O)(CH₂)₃—ONO₂.
 37. The compound of claim 31,wherein R₁ is —(C═O)(CH₂)₂—CH(NH₂)CH₂ONO₂.
 38. The compound of claim 31,wherein R₂ is a C₁-C₃ alkyl.
 39. The compound of claim 31, wherein R₃ isH and X is absent.
 40. The compound of claim 31, wherein R₃ is halogenand X is absent.
 41. The compound of claim 31, wherein R₃ is H and X isO.
 42. The compound of claim 31, wherein R₃ is C₁-C₆ alkyl and X is O.43. The compound of claim 31, wherein R₄ is H and Y is absent.
 44. Thecompound of claim 31, wherein R₄ is H and Y is O.
 45. The compound ofclaim 31, wherein R₄ is halogen and Y is absent.
 46. The compound ofclaim 31, wherein R₄ is C₁-C₆ alkyl and Y is O.
 47. The compound ofclaim 31, wherein R₅ is H and Z is absent.
 48. The compound of claim 31,wherein R₅ is H and Z is O.
 49. The compound of claim 31, wherein R₅ ishalogen and Z is absent.
 50. The compound of claim 31, wherein R₅ isC₁-C₆ alkyl and Z is O.
 51. A pharmaceutical composition, comprising acompound of claim 31 and a pharmaceutically acceptable excipient.
 52. Amethod of treating a mental health disease or disorder, the methodcomprising administering a therapeutically effective amount of acompound of claim 31 to a patient in need thereof.